Most successful human vaccines elicit protective antibodies. CD4+ T cell help is essential for a strong antibody response, especially against poorly immunogenic polysaccharide antigens. To accomplish this, polysaccharide antigens are typically conjugated to highly immunogenic T cell epitopes. Unfortunately, this approach is expensive, only targets a subset of capsular polysaccharide antigens, and depends on allelically variable CD4+ T cell help. We and others have recently identified a new source for help for B cells which can be harnessed to overcome these limitations, the invariant Natural Killer T (iNKT) cells. iNKT cells are an innate glycolipid-specific lymphocyte subset of T cells restricted to the non-polymorphic antigen presenting molecule CD1d which rapidly produce cytokines when activated. Because CD1d is non-polymorphic, or the same in all people, iNKT cells should respond to glycolipids equally well in everyone. Furthermore, glycolipids are overwhelmingly safe for humans and can serve as robust adjuvants for co-administered protein and polysaccharide antigens, especially when incorporated in nanoparticles. Nanoparticle vaccines can be made of safe, well-studied, biodegradable polymers, enhance the activity of encapsulated glycolipid adjuvants 1000 fold, and can be embedded with B cell antigens to facilitate their targeting and uptake by a relevant B cell subpopulation. The overall objective of this proposal is to use nanoparticle delivery of glycolipid adjuvant plus polysaccharide B cell antigen to protect mice against systemic infection with an encapsulated pathogen. In Aim 1 we will vaccinate mice with glycolipid plus polysaccharide embedded nanoparticles to assess which route of administration induces high titer class-switched antibodies, and protects best against two different in vivo murine models of Streptococcus pneumoniae infection. In Aim 2 we will use mice to compare how well soluble vs nanoparticle-embedded glycolipids enhance protective antibody responses induced by current human S. pneumoniae polysaccharide-based vaccines. We will also culture human peripheral blood cells to test which form of glycolipid adjuvant best enhances human polysaccharide-specific B cell responses. If successful, this line of research will drive the development of a widely applicable iNKT cell-targeted vaccine strategy which, given the non-polymorphic nature of CD1d, may be universally effective in all people. In turn, this vaccine can protect and improve human health, reduce the burdens of illness, and enhance the nation's economic well-being.